Method of using gonadorelin for the treatment of benign prostatic hyperplasia

ABSTRACT

Herein is described a method of treating benign prostatic hyperlasia without affecting testicular weight in a male mammal by administering an effective amount of gonadorelin.

BACKGROUND OF THE INVENTION

This invention relates to a new method of using gonadorelin. Thisdecapeptide is useful for treating benign prostatic hyperplasia withoutaffecting testicular weight. Gonadorelin is the generic name forluteinizing hormone-releasing factor (LH-RH) having the chemicalstructure, Pyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂.

The structure of gonadorelin is well known and a number of synthesis ofthe decapeptide are reported, for example, see H. U. Immer et al., U.S.Pat. No. 3,835,108, issued Sept. 10, 1974, incorporated herein byreference. Although numerous medical uses of gonadorelin have beenreported, this invention describes a new use of the decapeptide fortreating benign prostatic hyperplasia.

A few nonapeptide derivatives of gonadorelin have been reported to beeffective for treating various tumors, for example, E. S. Johnson and J.H. Seely, U.S. Pat. No. 4,002,738, issue Jan. 11, 1977; E. S. Johnsonand J. H. Seely, U.S. Pat. No. 4,071,622, issued Jan. 31, 1978 and E. S.Johnson, U.S. Pat. No. 4,005,194, issued Jan. 25, 1977. The first twoU.S. patents relate to method of reducing the size of mammary and7,12-dimethylbenzanthracene tumors by administering certainnonapeptides. The third U.S. patent, U.S. Pat. No. 4,005,194, describesnonapeptide derivatives which are effective for treating prostatichyperplasia, some of these nonapeptides have an undesirable side effectwherein a marked reduction of the testicular weight is also observed, C.Auclair et al., Endocrinology, 101, 1890 (1977) and C. Auclair et al.,Biochem. Biophys. Res. Commun., 76, 855 (1977).

SUMMARY OF THE INVENTION

Herein is described a method of reducing or preventing undesirableprostatic growth in a male mammal by administering to the mammal aneffective amount of a decapeptide of the formulaPyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂ to reduce or preventprostatic growth. This method is especially useful for the treatment ofbenign prostatic hyperplasia.

DETAILS OF THE INVENTION

In general the abbreviations used herein for designating the amino acidsare based on recommendations of the IUPAC-IUB Commission on BiochemicalNomenclature, see Biochemistry, 11, 1726-1732 (1972). For instance, Pyr,His, Trp, Ser, Tyr, Leu, Arg, Pro and Gly represent the "residues" of5-oxo-L-proline, L-histidine, L-tryptophan, L-serine, L-tyrosine,L-leucine, L-arginine, L-proline and glycine respectively. The term"residue" refers to a radical derived from the corresponding α-aminoacid by eliminating the hydroxyl of the carboxy group and one hydrogenof the α-amino group.

For reducing or preventing excess prostatic growth in a male mammal,gonadorelin is administered to the mammal at a parenteral dose in therange of about 0.035 mg to 11.0 mg per kilogram of body weight per day.A preferred parenteral dose is in the range of about 0.080 mg to 2.0 mgper kilogram of body weight per day. Gonadorelin can be parenterallyadministered to the mammal by intravenous injection or subcutaneousinjection, preferably subcutaneously. A preferred vehicle in which toadminister it is physiological saline with or without 1% gelatin. Othersuitable parenteral compositions of gonadorelin are described in theabove cited U.S. Pat. No. 3,835,108.

Daily administration of gonadorelin induces a significant decrease ofthe weight of the seminal vesicle and ventral prostate without affectingtesticular weight. Thus, gonadorelin is useful for treating benignprostatic hyperplasia at a dose which does not affect testicular weight.

The following example illustrates further this invention.

ANIMALS

Adult male Sprague-Dawley rats weighing 275-325 g upon arrival wereobtained from Canadian Breeding Laboratories, St. Constant, Quebec,Canada. All animals were housed 2 per cage in an air-conditioned (21±1°C.; 45-50% humidity) and light (12 hours light, 12 hoursdarkness)-controlled room and given food and water ad libitum.

TREATMENTS

Groups of rats (10 per group) were injected subcutaneously daily for 3consecutive weeks with gonadorelin hydrochloride in a vehicle of salinecontaining 1% (v/v) of gelatin, (0.2 ml) or the vehicle alone. Rats werekilled by decapitation 24 hours after the last injection. The testes,seminal vesicles and ventral prostate were removed, chilled, weighed andkept frozen at -20° C. until use.

RESULTS

Weights of the seminal vesicles and ventral prostate from the controland treated animals are given in Table 1. Weights of the testes from thecontrol and treated animals are given in Table 2.

                  TABLE 1.                                                        ______________________________________                                        Effect of a 3-week treatment with increasing doses                            of gonadorelin (LH-RH) on the weight of the                                   seminal vesicles and ventral prostate. Organ                                  weights are expressed in mg of wet weight.                                    Rats were injected s.c. daily with the                                        indicated dose of gonadorelin                                                 Or-          WEEKS OF TREATMENT                                               gan  TREATMENT   0        1      2      3                                     ______________________________________                                        Se-  Control     295±10                                                                              305±10                                                                            354±10                                                                            353±16                             mi-  LH-RH 25μg        281±14                                                                            247±9**                                                                           260±13**                           nal                                                                                LH-RH 250μg       298±10                                                                            249±18**                                                                          210±8**                            Vesi-                                                                         cles LH-RH 2500μg       265±10*                                                                          236±13**                                                                          225±9**                            (mg)                                                                          ______________________________________                                             Control     342±25                                                                              394±24                                                                            490±                                                                              490±31                             Ven- LH-RH 25μg        359±23                                                                            415±31*                                                                           378±13**                           tral                                                                               LH-RH 250μg       360±26                                                                            380±38**                                                                          370±25**                           Pros-                                                                         tate LH-RH 2500μg       325±12*                                                                          355±31**                                                                          373±18**                           (mg)                                                                          ______________________________________                                          *P<0.05 experimental vs control of the same week.                            **P<0.01 experimental vs control of the same week.                       

                                      TABLE 2.                                    __________________________________________________________________________    Effect of a 3-week treatment with increasing doses of gonadorelin             (LH-RH) on the weight of the testes. Organ weights are expressed              in g of wet weight. Rats were injected s.c. daily with the                    indicated dose of gonadorelin.                                                            WEEKS OF TREATMENT                                                Organ                                                                             TREATMENT                                                                             0     1     2       3                                             __________________________________________________________________________    Testes                                                                            Control 2.99 ± 0.09                                                                      2.81 ± 0.14                                                                      3.16 ± 0.10                                                                        3.14 ± 0.14                                    LH-RH 25μg 2.79 ± 0.12                                                                      3.06 ± 0.05                                                                        3.11 ± 0.14                                    LH-RH 250 μg                                                                             3.01 ± 0.08                                                                      2.88 ± 0.14                                                                        3.17 ± 0.10                                    LH-RH 2500μg                                                                             2.75 ± 0.12                                                                        2.65 ± 0.09**                                                                    2.74 ± 0.10**                              (g)                                                                           __________________________________________________________________________     **P<0.01 experimental vs control of the same week.                       

Tables 1 and 2 show that daily subcutaneous administration to male ratsof gonadorelin up to three weeks significantly decreases the weight ofseminal vesicles and ventral prostate weight while not affecting thetesticular weight of the animals. Daily doses of 25 μg and 250 μg (i.e.0.08 mg and 0.8 mg per kilogram of body weight) are particularlyeffective in showing this selective effect. The selective effect issurprising in view of the reports that potent analogs of LH-RH such as[D-Ala⁶, des-Gly-NH₂ ¹⁰ ]-LH-RH ethylamide and [D-Leu⁶, des-Gly-NH₂ ¹⁰]-LH-RH ethylamide, reported in U.S. Pat. No. 4,005,194, noted above, donot show such a selectivity, see L. Cusan et al., Endocrinology, 104,1369 (1979) and C. Auclair et al., Endocrinology, 101, 1890 (1977).

Accordingly, the results obtained with gonadorelin demonstrate clearlythat gonadorelin can be used for treating prostatic hypertropy without adeleterious effect on the testes.

I claim:
 1. A method of reducing or preventing the undesirable prostaticgrowth of benign prostatic hyperplasia in a male mammal withoutaffecting testicular growth which comprises parenterally administeringto said mammal about 0.035 mg to 9.0 mg per kilogram of body weight perday of a decapeptide of the formulaPyr-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂ to reduce or prevent saidprostatic growth.
 2. A method of claim 1 wherein said decapeptide isadministered at a parenteral dose of about 0.080 mg to 2.0 mg perkilogram of body weight per day.
 3. A method of claim 1 wherein saiddecapeptide is administered at a parenteral dose of about 0.080 mg to0.80 mg per kilogram of body weight per day.